Conventional therapeutic methods for cancers include surgical therapy, chemotherapy with anticancer agents, radiotherapy, and therapeutic methods comprising a combination thereof. However, these methods are known to pose problems, including the inability to cope with cancer cell metastasis by surgical procedures, and attacking not only cancer cells, but also normal cells, to cause severe adverse effects and resistance to chemotherapy and radiotherapy as supplements to surgical procedures.
Amid this situation, investigations have recently been conducted on therapeutic methods for eliminating cancer cells by enhancing the immune system that is intrinsically present in the living organism, as a new therapeutic method for cancers. For example, clinical investigations using non-specific immunity activators (e.g., Krestin, Bestatin and the like), cytokine therapies (e.g., interferons, interleukins and the like), antibody therapies (e.g., Herceptin and the like), immune cell therapies (e.g., dendritic cell vaccine therapy, peptide vaccine therapy and the like) and the like are being conducted. In particular, an immune cell therapy aiming at activating cytotoxic T cells (Cytotoxic T lymphocyte: CTL) has recently been attracting attention. In that method, immature T cells recognize a complex of a major histocompatibility complex (MHC) molecule and an antigen peptide (e.g., fragmented cancer cell antigens and the like) presented by antigen-presenting cells (e.g., dendritic cells, macrophages and the like); at the same time a signal comes from a co-stimulatory molecule, whereby the immature T cells are induced to mature T cells exhibiting specific cytotoxicity for the presented complex, i.e., CTL. Dendritic cell vaccine therapy is a method wherein CTLs are efficiently induced by administering antigen-presented dendritic cells in culture, but problems such as those related to the use of a culture broth containing fetal calf serum and the route of administration are of concern. Peptide vaccine therapy is a method wherein an antigen peptide(s) derived from an inactivated cancer cell or a microorganism-infected cell is administered to promote the activation of CTLs that specifically recognize the antigen. Furthermore, with the use of an inactivated virus fragment or a microbial peptide such as protozoan peptide as the antigen peptides, immune cell therapies are applied not only to cancers, but also to microbial infectious diseases.
To date, more efficient and safer immune cell therapies comprising a combination thereof have been developed. For example, a method of transdermal immunotherapy has been developed wherein a corneal layer is removed using a highly adhesive tape to activate epidermal Langerhans cells, a type of dendritic cell, and antigen peptides are applied to the skin thus deprived of the corneal layer to induce CTLs in the living organism (see Patent Document 1 and Non-patent Documents 1 and 2).
Meanwhile, it is known that EP4 agonists, which bind specifically to EP4 receptor, subtype of PGE2 receptors, directly inhibit the proliferation of gastric cancer cells (see Non-patent Document 3), promote the maturation and migration of epidermal Langerhans cells being antigen-presenting cells to mediate the exacerbation of contact dermatitis (see Non-patent Document 4), and are useful as a therapeutic agent for autoimmune diseases such as rheumatism (see Patent Document 2). It is also known that EP4 antagonists are useful in the prevention and/or treatment of cancers (carcinogenesis, cancer growth, cancer visceral metastasis, cancer bone metastasis, hypercalcemia induced by cancer bone metastasis, and the like) (see Patent Document 3).
However, these documents do not state or suggest that EP4 agonists exhibit immunopotentiation via activation of cytotoxic T cells, particularly that EP4 agonists alone are useful in cancers (particularly melanoma), viral infections and the like on the basis of this immunopotentiating action.
[Patent Reference 1] Japanese Patent No. 3879785
[Patent Reference 2] International Publication No. 2003/009872
[Patent Reference 3] International Publication No. 01/062708
[Non Patent Reference 1] Proceedings of the natural academy sciences of USA, Vol. 97, 371-376, 2000
[Non Patent Reference 2] Cancer research, Vol. 66, 10136-10144, 2006
[Non Patent Reference 3] The journal of laboratory and clinical medicine, Vol. 140, 92-102, 2002
[Non Patent Reference 4] Nature medicine, Vol. 9, 744-749, 2003